Use of agonists of type-2 dopaminergic receptors in treatment of conditions caused by elevated vascular endothelial growth factor levels

ABSTRACT

The present invention relates to a use of type-2 dopaminergic receptor agonists in treatment of eye diseases caused by an elevated level of vascular endothelial growth factor (VEGF), particularly in treatment or prevention of diseases of an eye retina resulting from an increase in permeability of blood vessels and their angiogenesis using cabergoline, a dopaminergic D2 receptor agonist.

The present invention relates to use of type-2 dopaminergic receptoragonists in treatment of eye diseases caused by an elevated level ofvascular endothelial growth factor (VEGF), particularly in treatment orprevention of retinal disorders resulting from an increase inpermeability of blood vessels and their angiogenesis.

Eye diseases, in which an increase in permeability of blood vessels andtheir angiogenesis occur, include a multitude of diseases, mainly of theretina, such as diabetic macular edema, diabetic retinopathy,age-related macular degeneration, retinal artery occlusion or retinalvein occlusion.

Diabetic macular edema (DME) develops in patients with prolongeddiabetes and more advanced presentation of diabetic retinopathy. Itoccurs in about 14% of diabetics. The frequency of DME occurrence isdepends on stage of retinopathy and diabetes type and duration. After 25years of diabetes DME occurs in about 30% of patients with type 1 andtype 2 diabetes treated with insulin and in about 15% of patients withtype 2 diabetes treated with oral anti-diabetic medication. Diabeticmacular edema is defined by a presence of liquid or hard exudates within1 dd (disc diameter of the optic nerve) from the center of the macula.

Diabetic retinopathy (DR) is the most common cause of blindness indeveloped countries nowadays. It is the result of the increase indiabetes prevalence in those countries. According to WHO in the year2002 diabetic retinopathy was the cause of blindness in 1.8 millionpeople (4.8%) worldwide. In USA, every year, it becomes the reason forthe loss of vision for about 12-24 thousands of patients suffering fromdiabetes. From a clinical point of view DR has few variants, such asnon-proliferative retinopathy, pre-proliferative retinopathy, diabeticmaculopathy, proliferative retinopathy and advanced diabeticretinopathy. In most of these cases edema of the retina occurs and, incase of proliferative forms, proliferation of pathological bloodvessels.

Age-related macular degeneration (AMD) is the main reason of the loss ofvision in adults over 50 years old. It occurs in 8.8% of the population,more frequently in females, and its occurrence increases with age and itaffects almost 28% of people over age 75. It affects 50 million peopleglobally. Due to population ageing the problem of AMD increases andabout 10% of people over 45 years old are endangered by the disease. Theso-called dry form of AMD makes up 90% of AMD cases and causes atrophiclesions within the macula and gradual loss of vision. In 10% of patientswith AMD the wet (exudative) AMD form occurs, which causes blood vesselcarcinogenesis in retina and choroid (choroidal neovascularization; CNV)and leads to a rapid vision worsening or vision loss.

Retinal artery occlusion, or its branch occlusion, is a relatively rarecondition. It is characterized by a rapid and pain-less loss of vision.In case of quick treatment a complete or partial recovery of the visionis achieved. One of the complications of the central retinal arteryocclusion is the proliferation of pathological blood vessels in eyetissues.

Retinal vein occlusion occurs when central retinal vein (central retinalvein occlusion—CRVO) or its branch (branch retinal vein occlusion BRVO)is blocked. It leads to different kinds of vision degradation. CRVO andBRVO are the second most common vascular diseases of the retina. Theform with ischemia is less common than the form without it. Retinal veinocclusions occur with incidence of about 2 cases per 1000 people over 40years of age and more than 5 cases per 1000 people over 64 years of age.As with central retinal artery occlusion in case of retinal veinocclusion late complications are possible, involving carcinogenesis ofpathological blood vessels in the retina and in other eye tissues e.g.in drainage angle or iris.

Function of the Vascular Endothelial Growth Factor (VEGF) in theIncrease in Permeability of Blood Vessels and Angiogenesis of BloodVessels.

VEGF is a group of cytokines comprising a group of substances thatinclude: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F and PIGF(placental growth factor). The VEGF cytokines act through specificreceptors. Currently a few of types thereof are known such as: VEGFR-1,VEGFR-2, FLK-1 and VEGFR-3. VEGF binds with receptors, which triggers acascade of chemical reactions, which finally lead to an increase inpermeability of blood vessels and stimulation of proliferation andmigration of epithelial cells of blood and lymphatic vessels. Migratingcells of the endothelium create tubular structures, which are the budsof new blood vessels.

Secretion of VEGF is stimulated by many factors. These includepro-inflammatory cytokines, such as interleukin 1 (IL-1) and interleukin6 (IL-6), substances secreted by tissues during the course of hypoxia e.g. hypoxia-induced factor (HIF-1), other growth factors e. g.transforming growth factor (TGF), insulin-like growth factor (IGF),fibroblast growth factor (FGF) and platelet-derived growth factor(PDGF).

The process of angiogenesis in eye tissues occurs mostly in low-oxygensupply conditions due to e. g. a decrease in blood flow or an increasein tissue demand for oxygen and in chronic tissue inflammation, whenfactors promoting secretion of VEGF are released. The blood vessels thatare created in that way are responsible for the occurrence, inter alia,of collateral circulation in cardiac muscle, which plays a veryimportant role in supporting correct tissue oxidation.

Unfortunately, newly created blood vessels are not always beneficial forfunctioning of organs. For example, in the case of eye tissues, thereoccurs a pathological growth of blood vessels and breakdown ofblood-retinal barrier, which in normal conditions prevents excessivepenetration of fluid from blood vessels to tissues.

Function of the Vascular Endothelial Growth Factor (VEGF) in theIncrease in Permeability of Blood Vessels and Angiogenesis of BloodVessels in Eye Tissues.

An increase in secretion of VEGF occurs in diabetic retinopathy(proliferative and pre-proliferative), wet age-related maculardegeneration, central retinal artery occlusion, central (or branch)retinal vein occlusion. The released VEGF increases permeability ofblood vessels, which leads to breakdown of blood-retinal barrier,increase of in penetration of fluid to the retina and edema thereof. Anincrease in intra-tissue pressure in the retina causes breakdown oftissue and atrophy thereof. VEGF also stimulates formation of newvessels, which are characterized by high permeability, which furtherincreases edema of surrounding tissues. Newly created blood vesselsdisturb the physiological layout and course of blood vessels in theretina and the choroid of the eye and grow into vessel-free spaces e. g.the vitreous body. The walls of blood vessels formed during angiogenesisare fragile, they often break and cause hemorrhages into the vitreousbody.

Currently, in order to decrease the edema of eye tissues and to inhibitangiogenesis inhibitors of VEGF or its receptors are used, such asranibizumab (recombinant humanized monoclonal antibody fragment againstVEGF-A), bevacizumab (recombinant humanized monoclonal antibody againstVEGF-A) and aflibercept (Fc fragment of a receptor for VEGF). They areadministered as repeated intravitreal injections, usually with one ortwo month intervals. The injection form of administration of the VEGFinhibitors requires sterile administration conditions, limits the numberof potential patients and has a high risk of side effects.

Therefore, there is still a need for development of new means fortreatment of eye diseases caused by an elevated level of vascularendothelial growth factor (VEGF), which would be effective andeasily-available and their way of administration would be easier.

In order to find the solution for this problem the inventor of thepresent invention has conducted extensive research and has unexpectedlyfound that agonists of the type-2 dopaminergic receptors may be usefulin treatment of eye diseases caused by an elevated level of vascularendothelial growth factor (VEGF), particularly in treatment orprevention of diseases of eye tissues, resulting from an increase inpermeability of blood vessels and their carcinogenesis. Additionally theinventor has found that the most preferred agonist of a dopaminergic D2receptor is cabergoline.

Thus, the present invention relates to a use of type2 dopaminergicreceptor agonists such as cabergoline in treatment of eye diseasescaused by an elevated level of VEGF in eye tissues, which leads to theiredema and to formation of pathological blood vessels.

The invention thus relates to a use of cabergoline and other agonists ofa dopaminergic D2 receptor in treatment of eye diseases caused by anelevated level of vascular endothelial growth factor.

The present invention also relates to a possibility of using cabergolineand other agonists of a dopaminergic D2 receptor in treatment of eyediseases caused by an elevated level of vascular endothelial growthfactor, in particular of diseases of an eye retina caused by an increasein permeability of blood vessels and/or their angiogenesis.

The invention also relates to a pharmaceutical composition containing asan active ingredient cabergoline or other agonists of a dopaminergic D2receptor for use in treatment of eye diseases caused by an elevatedlevel of vascular endothelial growth factor, in particular diseases ofan eye retina caused by an increase in permeability of blood vesselsand/or their carcinogenesis.

Preferably, the composition according to the invention is for oraladministration.

Function of Dopaminergic D2 Receptors in Inhibition of VEGF Effects.

It has been shown in experimental research that dopamine acting throughdopamine D2 receptors inhibits permeability of blood vessels andproliferation and migration of vascular endothelial cells. This activityis presumably achieved by decreasing the number of VEGF-2 receptors anda decrease in affinity of VEGF-2 receptors to VEGF. The aboveobservations are supported by clinical data. The agonist of dopaminergicD2 receptorscabergoline is successfully used in prevention and treatmentof ovarian hyperstimulation syndrome (OHSS). OHSS is related to anincreased VEGF secretion by granulosa cells of an ovarian follicle dueto hormonal stimulation of ovulation and to an increase in blood vesselpermeability resulting from activation of the VEGF-2 receptor.

Pharmacological Effects of Dopaminergic D2 Receptor Agonist—Cabergoline.

Cabergoline, having a structure according to the formula shown below, isa dopaminergic D2 receptor agonist.

Cabergoline is used in treatment of disorders related to an excessiveprolactin secretion (e. g. menstrual disorders, lack of ovulation,galactorrhea), pituitary adenoma, idiopathic hyperprolactinemia, emptysella syndrome. Cabergoline is used in treatment of the above mentioneddisorders in doses from 0.5 mg once per day or from 0.25 mg to 4.5 mgonce per week. Cabergoline is successfully used in prevention andtreatment of OHSS as well, with a daily dose of 0.5 mg-1 mg over 7-14days since the stimulation of ovulation.

Polish patent application P.343593 relates to use of cabergoline intreatment of a restless legs syndrome, while in polish patentapplications P.344574, P.380898 and P.383475 use of cabergoline incombination with pramipexole for treatment of multiple systems atrophy,progressive supranuclear palsy and Parkinson's disease were described.

EXAMPLE 1

The Effects of Administration of Cabergoline on Permeability ofBlood-Retinal Barrier and on Retinal Thickness in an Experimental Modelfor Diabetic Retinopathy

The research was conducted on an experimental model of Wistar strainrats. In order to cause diabetes the rats were injectedintraperitoneally with streptozocin at a dose of 60 mg/kg b.w. After 30days since administration of streptozocin blood glucose level waschecked and only rats with the blood glucose levels of over 250 mg %were qualified for the experiment.

In the course of the experiment, the following parameters were assessed:permeability of blood-retinal barrier using the dextran method (BRB) andthe thickness of the retina using optical coherence tomography (OCT).

In the experiment, 4 experimental groups were compared: healthy animalswithout cabergoline administration, healthy animals with cabergolineadministration (14 days of use), animals with diabetes withoutcabergoline, animals with diabetes with cabergoline (14 days of use).Cabergoline was administered to the animals in oral form at a dose of0.05 mg/kg b.w. over 14 days.

Experimental group/Parameter BRB (μl/g/min) OCT (μm) Control group 25.6± 4.5  272 ± 10 Group with diabetes without cabergoline 54.6 ± 12.1 383± 29 Healthy group with cabergoline 22.4 ± 7.5  281 ± 14 Group withdiabetes with cabergoline 35.8 ± 10.6 320 ± 35

EXAMPLE 2

The Effects of Administration of Cabergoline on Permeability ofBlood-Retinal Barrier and Retinal Thickness in an Experimental Model forCentral Retinal Vein Occlusion.

The research was conducted on an experimental model of Wistar strainrats. Central retinal vein occlusion was performed using a 532 nm laser.

In the course of the experiment, the following parameters were assessed:permeability of blood-retinal barrier using the dextran method (BRB) andthe thickness of the retina using optical coherence tomography (OCT).

In the experiment, 4 experimental groups were compared: healthy animalswithout cabergoline administration, healthy animals with cabergolineadministration (14 days of use), animals with central retinal veinocclusion without cabergoline, animals with central retinal veinocclusion with cabergoline (14 days of use). Cabergoline wasadministered to the animals in oral form at a dose of 0.05 mg/kg b.w.over 14 days.

Experimental group/Parameter BRB (μl/g/min) OCT (μm) Control group 23.2± 6.8  235 ± 14 Group with central retinal vein occlusion 48.9 ± 14.6419 ± 36 without cabergoline Healthy group with cabergoline 25.1 ± 4.2 258 ± 13 Group with central retinal vein occlusion 33.3 ± 12.9 343 ± 28with cabergoline

EXAMPLE 3

The Effects of Administration of Cabergoline on Permeability ofBlood-Retinal Barrier and Retinal Thickness in an Experimental Model forChoroidal Neovascularization (CNV).

The research was conducted on an experimental model of Wistar strainrats. Choroidal neovascularization (CNV) was performed byphotocoagulation of the retina using a 532 nm laser.

In the course of the experiment, the following parameters were assessed:permeability of blood-retinal barrier using the dextran method (BRB) andthe thickness of the retina using optical coherence tomography (OCT).

In the experiment, 4 experimental groups were compared: healthy animalswithout cabergoline administration, healthy animals with cabergolineadministration (14 days of use), animals with CNV without cabergoline,animals with CNV with cabergoline (14 days of use). Cabergoline wasadministered to the animals in oral form at a dose of 0.05 mg/kg b.w.over 14 days.

Experimental group/Parameter BRB (μl/g/min) OCT (μm) Control group 27.3± 9.2  242 ± 28 Group with CNV without cabergoline 43.1 ± 9.9  362 ± 32Healthy group with cabergoline 28.5 ± 6.6  221 ± 22 Group with CNV withcabergoline 37.4 ± 15.2 283 ± 17

1. Use of type-2 dopaminergic receptor agonists in treatment of eyediseases caused by an elevated level of vascular endothelial growthfactor.
 2. The use according to claim 1, wherein the eye disease is adisease of an eye retina caused by an increase in permeability of bloodvessels and/or their angiogenesis.
 3. The use according to claim 1,wherein the type-2 dopaminergic receptor agonist is cabergoline.
 4. Useof cabergoline in treatment of eye diseases caused by an elevated levelof vascular endothelial growth factor.
 5. Cabergoline for use intreatment of eye diseases caused by an elevated level of vascularendothelial growth factor.
 6. Cabergoline for use according to claim 5,wherein the eye disease is a disease of an eye retina caused by anincrease in permeability of blood vessels and/or their angiogenesis. 7.A pharmaceutical composition comprising cabergoline as an activeingredient for use in treatment of eye diseases caused by an elevatedlevel of vascular endothelial growth factor.
 8. The compositionaccording to claim 7, for use, wherein the eye disease is a disease ofan eye retina caused by an increase in permeability of blood vesselsand/or their angiogenesis.
 9. The composition according to claim 7 fororal administration.